It belongs to the family of synthetic chemicals called pyrethroids and functions as a neurotoxin, affecting neuronmembranes by prolonging sodium channel activation. It is not known to rapidly harm most mammals or birds, but is toxic to fish and cats. In cats it may induce hyperexcitability, tremors, seizures, and death.[1] In general, it has a low mammalian toxicity and is poorly absorbed by skin.[2]

Medical use

Permethrin is available for topical use as a cream or lotion. It is indicated for the treatment and prevention in exposed individuals of head lice and treatment of scabies.[4]

For treatment of scabies: Adults and children older than 2 months are instructed to apply the cream to the entire body from head to the soles of the feet. Wash off the cream after 8–14 hours. In general, one treatment is curative.[5]

For treatment of head lice: Apply to hair, scalp, and neck after shampooing. Leave in for 10 minutes and rinse. Avoid contact with eyes.[6]

Pest control

In agriculture, permethrin is mainly used on cotton, wheat, maize, and alfalfa crops. Its use is controversial because, as a broad-spectrum chemical, it kills indiscriminately; as well as the intended pests, it can harm beneficial insects including honey bees, and aquatic life.[7]

Permethrin is used in tropical areas to prevent mosquito-borne disease such as dengue fever and malaria. Mosquito nets used to cover beds may be treated with a solution of permethrin. This increases the effectiveness of the bed net by killing parasitic insects before they are able to find gaps or holes in the net. Military personnel training in malaria-endemic areas may be instructed to treat their uniforms with permethrin, as well.

Permethrin is the most commonly used insecticide worldwide for the protection of wool from keratinophagous insects such as Tineola bisselliella.[8]

Side effects

Safety

Permethrin has little systemic absorption, and is considered safe for topical use in adults and children over the age of 2 months. The FDA has assigned it as pregnancy category B. Animal studies have shown no effects on fertility or teratogenicity, but studies in humans have not been performed. The excretion of permethrin in breastmilk is unknown, and breastfeeding is recommended to be temporarily discontinued during treatment.[6]

Pharmacokinetics

Absorption

Absorption of topical permethrin is minimal. One in vivo study demonstrated 0.5% absorption in the first 48 hours based upon excretion of urinary metabolites.[9]

Distribution

Distribution of permethrin has been studied in rat models, with highest amounts accumulating in fat and the brain.[10] This can be explained by the lipophilic nature of the permethrin molecule.

Metabolism

Metabolism of permethrin occurs mainly in the liver, where the molecule undergoes oxidation by the cytochrome P450 system, as well as hydrolysis, into metabolites.[9]
Elimination of these metabolites occurs via urinary excretion.

Military use

To better protect soldiers from the risk and annoyance of biting insects, the US[11] and British[12] armies are treating all new uniforms with permethrin.

Permethrin is extremely toxic to fish and aquatic life in general, so extreme care must be taken when using products containing permethrin near water sources.

Permethrin is also highly toxic to cats, and flea and tick-repellent formulas intended and labeled for (the more resistant) dogs may contain permethrin and cause feline permethrin toxicosis in cats.[13]

Permethrin is listed as a "restricted use" substance by the US Environmental Protection Agency (EPA)[14] due to its high toxicity to aquatic organisms,[15]
so permethrin and permethrin-contaminated water should be properly disposed. Permethrin is quite stable, having a half life of 51–71 days in an aqueous environment exposed to light. It is also highly persistent in soil.[16]

Human exposure

According to the Connecticut Department of Public Health, permethrin "has low mammalian toxicity, is poorly absorbed through the skin, and is rapidly inactivated by the body. Skin reactions have been uncommon."[17]

Permethrin does not present any notable genotoxicity or immunotoxicity in humans and farm animals, but is classified by the EPA as a likely human carcinogen, based on reproducible studies in which mice fed permethrin developed liver and lung tumors.[19] Carcinogenic action in nasalmucosal cells due to inhalation exposure is suspected, due to observed genotoxicity in human tissue samples, and in rat livers the evidence of increased preneoplastic lesions raises concern over oral exposure.[20][21]

Animal studies by Bloomquist et al.[22] suggest a possible link of permethrin exposure to Parkinson's disease, including very small exposures:

2002 study – "Our studies have documented low-dose effects of permethrin, doses below one-one thousandth of a lethal dose for a mouse, with effects on those brain pathways involved in Parkinson's disease [...] We have found effects consistent with a pre-parkinsonsian condition, but not yet full-blown parkinsonism."[23][24]

However, a 2007 study by the same researcher concluded "little hazard to humans" existed.

2007 study – "long-term, low-dose exposure to permethrin alone did not cause signs of neurotoxicity to striataldopaminergicneural terminals, or enhance the effects of MPTP. We conclude that, under typical use conditions, permethrin poses little parkinsonian hazard to humans, including when impregnated into clothing for control of biting flies"[25]

Domestic animals

Pesticide-grade permethrin is toxic to cats. Many cats die after being given flea treatments intended for dogs, or by contact with dogs having recently been treated with permethrin.[27]

Toxic exposure of permethrin can cause several symptoms, including convulsion, hyperaesthesia, hyperthermia, hypersalivation, and loss of balance and coordination. Exposure to pyrethroid-derived drugs such as permethrin requires treatment by a veterinarian, otherwise the poisoning is often fatal.[28][29] This intolerance is due to a defect in glucuronosyltransferase, a common detoxification enzyme in other mammals (that also makes the cat intolerant to paracetamol and many essential oils).[30] The use of any external parasiticides based on permethrin is contraindicated for cats. (Cat ecotoxicology: cutaneous 100mg/kg - oral 200mg/kg.)

Synthesis

Numerous synthetic routes exist for the production of the DV-acid ester precursor. The pathway known as the Kuraray Process uses four steps.[32] In general, the final step in the total synthesis of any of the synthetic pyrethroids is a coupling of a DV-acid ester and an alcohol. In the case of permethrin synthesis, the DV-acid cyclopropanecarboxylic acid, 3-(2,2-dichloroethenyl)-2,2-dimethyl-, ethyl ester, is coupled with the alcohol, m-phenoxybenzyl alcohol, through a transesterification reaction with base. Tetraisopropyl titanate or sodium ethylate may be used as the base.[32]

The alcohol precursor may be prepared in three steps. First, m-cresol, chlorobenzene, sodium hydroxide, potassium hydroxide, and copper chloride react to yield m-phenoxytoluene. Second, oxidation of m-phenoxytoluene over selenium dioxide provides m-phenoxybenzaldehyde. Third, a Cannizzaro reaction of the benzaldehyde in formaldehyde and potassium hydroxide affords the m-phenoxybenzyl alcohol.[32]

Brand names

It is marketed by Johnson & Johnson under the name Lyclear. In Nordic countries and North America, it is marketed under trade name Nix, often available over the counter.